Atonal protein homologue 1 (Atoh1 or atonal) is a proneural gene that encodes a basic helix-loop-helix (bHLH) domain-containing protein that seems to play an important role in cell fate determination in the development of the Drosophila nervous system (Jarman et al., Cell, 73:1307-1321, 1993). Atoh1 is evolutionarily conserved, with homologs identified in Tribolium castenium (the red flour beetle), Fugu rubripes (puffer fish), chicken (Cath1), mouse (Math1), and human (Hath1) (Ben-Arie et al., Hum. Mol. Gene., 5:1207-1216, 1996). Each of these homologs contain a bHLH domain that is identical in length and have high sequence identity to the Atoh1 bHLH domain. For example, the Hath1 and Math1 genes are almost identical in length. These molecules also have highly similar nucleotide sequences (86% identity) and highly similar bHLH amino acid sequences (89%). The bHLH domain of Cath1 is 97% and 95% identical to the bHLH domain of Hath1 and Math1, respectively. The bHLH of Cath1 is 67% identical to the Atoh1 bHLH domain. In contrast, the bHLH domains of other Drosophila encoded proteins share only 40-50% sequence identity.
Each of the mammalian Atoh1 homologs function as transcription factors that activate E box (CANNTG (SEQ ID NO:1)) dependent transcription (Arie et al., supra; Akazawa et al., J. Biol. Chem., 270:8730-8738, 1995) and function as critical positive regulators of cell fate determination in neural tissue and the gastrointestinal (GI) tract (Helms et al., Development, 125:919-928, 1998; Isaka et al., Eur. J. Neurosci., 11:2582-2588, 1999; Ben-Arie et al., Development, 127:1039-1048, 2000). In addition, Atoh1 is critical for auditory hair cell development from inner ear progenitor cells, as demonstrated by the absence of auditory hair cells in Atoh1 knockout animals (Bermingham et al., Science, 284:1837-1841, 1999).
Once activated, Atoh1 transcription is self perpetuating due to the binding of Atoh1 to the Atoh1 3′ enhancer (Helms et al., Development, 127:1185-1196, 2000), and the Atoh1 promoter is switched on in Atoh1 knockout mice (Bermingham et al., Science, 284:1837-1841, 1999; Tsuchiya et al., Gastroenterology, 132:208-220, 2007). These observation indicate that mechanisms to activate Atoh1, such as upstream regulators of Atoh1, must exist. Such upstream regulators of Atoh1 are likely to have important roles in the regulation of development in the central and peripheral nervous systems and in the intestinal epithelium, all of which rely on Atoh1 for differentiation.